The present invention relates to, inter alia, novel trifluoromethyl sulfonyl and trifluoromethyl sulfonamido compounds, their physiologically acceptable salts and prodrugs, which modulate the activity of protein phosphatases and uses thereof. The invention also relates to the use of compounds containing fluoromethyl sulfonyl groups to treat certain diseases. These compounds may be used as phosphate mimics to inhibit, regulate or modulate the activity of a phosphate binding protein in a cell. Thus, these mimics may be particularly useful in the treatment of phosphate binding protein associated disorders.
Phosphate derivatives are involved in a wide variety of cellular processes. Common phosphate derivatives include nucleotides (e.g. mono-, di- or tri-phosphate adenosine, guanine, cytosine, thymidine, or uridine, or cyclic derivatives) either naturally occurring or synthetic analogues. Other common cellular phosphate derivatives include co-factors such as thiamine pyrophosphate, NADPH, pyridoxal pyrophosphate, or coenzyme A; compounds involved in sugar metabolism such as glucose 6-phosphate, fructose 6-phosphate, compounds involved in fatty acid metabolism such as glycerol 3-phosphate; compounds involved in lipid biosynthesis such as isopentyl pyrophosphate, geranyl pyrophosphate or farnesyl pyrophosphate.
Another area involving phosphate binding proteins is cellular transduction. Cellular signal transduction is a fundamental mechanism whereby external stimuli that regulate diverse cellular processes are relayed to the interior of cells. The biochemical pathways through which signals are transmitted within cells comprise a circuitry of directly or functionally connected interactive proteins. One of the key biochemical mechanisms of signal transduction involves the reversible phosphorylation of residues on proteins. The phosphorylation state of a protein may affect its conformation and/or enzymatic activity as well as its cellular location. The phosphorylation state of a protein is modified through the reciprocal actions of protein kinases and protein phosphatases at various specific residues.
A common mechanism by which receptors regulate cell function is through an inducible kinase or phosphatase activity, including tyrosine kinase activity which is either endogenous to the receptor or is imparted by other proteins that become associated with the receptor. (Darnell et al., 1994, Science, 264:1415-1421; Heldin, 1995, Cell, 80:213-223; Pawson, 1995, Nature, 373:573-580). Protein tyrosine kinases (PTK) comprise a large family of transmembrane receptor and intracellular enzymes with multiple functional domains (Taylor et al., 1992, Ann. Rev. Cell Biol. 8:429-62). The binding of ligand allosterically transduces a signal across the cell membrane where, the cytoplasmic portion of the PTKs initiates a cascade of molecular interactions that disseminate the signal throughout the cell and into the nucleus. Many receptor protein tyrosine kinase (RTKs), such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) undergo oligomerization upon ligand binding, and the receptors self-phosphorylate (via autophosphorylation or transphosphorylation) on specific tyrosine residues in the cytoplasmic portions of the receptor (Schlessinger and Ullrich, 1992, Neuron, 9:383-91, Heldin, 1995, Cell, 80:213223). Cytoplasmic protein tyrosine kinases (CTKs), such as Janus kinases (e.g., JAK1, JAK2, TYK2) and Src kinases (e.g., src, lck, fyn) are associated with receptors for cytokines (e.g., IL-2, IL-3, IL-6, erythropoietin), interferons and antigens. These associated receptors also undergo oligomerization, and have tyrosine residues that become phosphorylated during activation, but the receptor polypeptides themselves do not possess kinase activity.
Like the PTKS, the protein tyrosine phosphatases (PTPs) comprise a family of transmembrane and cytoplasmic enzymes, possessing at least an approximately 230 amino acid catalytic domain containing a highly conserved active site with the consensus motif [I/V]HCXXXXXR[S/T] (SEQ ID NO: 1). The substrates of PTPs may be PTKs which possess phosphotyrosine residues or the substrates of PTKs. (Hunter, 1989, Cell, 58:1013-16; Fischer et al., 1991, Science, 253:401-6; Saito and Streuli, 1991, Cell Growth and Differentiation, 2:59-65; Pot and Dixon, 1992, Biochem. Biophys. Acta, 1136:35-43).
Transmembrane or receptor-like PTPs (RTPs) possess an extracellular domain, a single transmembrane domain, and one or two catalytic domains followed by a short cytoplasmic tail. The extracellular domains of these RTPs are highly divergent, with small glycosylated segments (e.g., RTPxcex1, RTPxcex5), tandem repeats of immunoglobulin-like and/or fibronectin type III domains (e.g., LAR) or carbonic anhydrase like domains (e.g., RTPxcex1, RTPxcex2). These extracellular features might suggest that these RTPs function as a receptor on the cell surface, and their enzymatic activity might be modulated by ligands. Intracellular or cytoplasmic PTPs (CTPs), such as PTP1C and PTP1D, typically contain a single catalytic domain flanked by several types of modular conserved domains. For example, PTP1C, a hemopoietic cell CTP, is characterized by two Src homology 2 (SH2) domains that recognize short peptide motifs bearing phosphotyrosine (pTyr).
In general, these modular conserved domains may influence the intracellular localization of the protein. SH2-domain containing proteins are able to bind pTyr sites in activated receptors and cytoplasmic phosphoproteins. Another conserved domain known as SH3 binds to proteins with proline-rich regions. A third type known as the pleckstrin-homology (PH) domain has also been identified. These modular domains have been found in both CTKs and CTPs as well as in noncatalytic adapter molecules, such as Grbs (Growth factor Receptor Bound), which mediate protein-protein interactions between components of the signal transduction pathway (Skolnik et al., 1991, Cell, 65:83-90; Pawson, 1995, Nature, 373:573-580).
Multiprotein signaling complexes comprising receptor subunits, kinases, phosphatases and adapter molecules are assembled in subcellular compartments through the specific and dynamic interactions between these domains and their binding motifs. Such signaling complexes integrate the extracellular signal with the ligand-bound receptor and relay the signal to other downstream signaling proteins or complexes in other locations inside the cell, including the nucleus (Koch et al., 1991, Science, 252:668-674; Pawson, 1994, Nature, 373:573-580; Mauro et al., 1994, Trends Biochem. Sci., 19:151-155; Cohen et al., 1995, Cell, 80:237-248).
The levels of phosphorylation required for normal cell growth and differentiation at any time are achieved through the coordinated action of phosphatases and kinases. Depending on the cellular context, these two types of enzymes may either antagonize or cooperate with each other during signal transduction. An imbalance between these enzymes may impair normal cell functions leading to metabolic disorders and cellular transformation.
For example, insulin binding to the insulin receptor, which is a PTK, triggers a variety of metabolic and growth promoting effects such as glucose transport, biosynthesis of glycogen and fats, DNA synthesis, cell division and differentiation. Diabetes mellitus, which is characterized by insufficient or a lack of insulin signal transduction, can be caused by any abnormality at any step along the insulin signaling pathway. (Olefsky, 1988, xe2x80x9cCecil Textbook of Medicine,xe2x80x9d 18th Ed., 2:1360-81).
It is also well known, for example, that the overexpression of PTKS, such as HER2, can play a decisive role in the development of cancer (Slamon et al., 1987, Science, 235:77-82) and that antibodies capable of blocking the activity of this enzyme can abrogate tumor growth (Drebin et al., 1988, Oncogene, 2:387-394). Blocking the signal transduction capability of tyrosine kinases such as FlK-1 and the PDGF receptor have been shown to block tumor growth in animal models (Millauer et al., 1994, Nature, 367:577; Ueno et al., 1991, Science, 252:844-848).
Relatively less is known with respect to the direct role of tyrosine phosphatases in signal transduction. However, PTPs have been linked to human diseases. For example, ectopic expression of RTPxcex1 produces a transformed phenotype in embryonic fibroblasts (Zheng et al., 1992, Nature, 359:336-339), and overexpression of RTPxcex1 in embryonal carcinoma cells causes the cells to differentiate into a cell type with a neuronal phenotype (den Hertog, et al., 1993, EMBO Journal, 12:3789-3798). The gene for human RTPxcex3 has been localized to chromosome 3p21 which is a segment frequently altered in renal and small lung carcinoma. Mutations may occur in the extracellular segment of RTPxcex3 which renders the RTP no longer responsive to external signals (LaForgia et al., 1993, Cancer Res., 53:3118-3124; Wary et al., 1993, Cancer Res., 52:478-482). Mutations in the gene encoding PTP1C (also known as HCP or SHP) are the cause of the moth-eaten phenotype in mice which suffer from severe immunodeficiency, and systemic autoimmune disease accompanied by hyperproliferation of macrophages (Schultz et al., 1993, Cell, 73:1445-1454). PTP1D (also known as Syp, SHP2 or PTP2C) has been shown to bind through SH2 domains to sites of phosphorylation in PDGFR, EGFR and insulin receptor substrate 1 (IRS-1). Reducing the activity of PTP1D by microinjection of anti-PTP1D antibody has been shown to block insulin or EGF-induced mitogenesis (Xiao et al., 1994, J. Biol. Chem., 269:21244-21248).
It has been reported that some of the biological effects of insulin can be mimicked by vanadium salts such as vanadates and pervanadates. Vanadates and pervanadates are known to be non-specific phosphatase inhibitors. However, this class of compounds is toxic because each compound contains a heavy metal (U.S. Pat. No. 5,155,031; Fantus et al., 1989, Biochem., 28:8864-71; Swarup et al., 1982, Biochem. Biophys. Res. Commun., 107:1104-9). Others have reported non-peptidyl inhibitors of protein tyrosine phosphatase 1B. Taylor et al., 1998, Bioorganic and Medicinal Chemistry, 6:1457-1468; For recent reviews, see xe2x80x9cProtein-Tyrosine Phosphatases: Structure, Mechanism, and Inhibitor Discovery.xe2x80x9d Burke, Jr. et al., 1998, Biopolymers (Peptide Science), 47:225-241; and xe2x80x9cPhosphotyrosyl-Based Motifs in the Structure-Based Design of Protein-Tyrosine Kinase-Dependent Signal Transduction Inhibitors.xe2x80x9d Burke, Jr. et al., 1997, Current Pharmaceutical Design, 3:291-304.
Trifluoromethyl sulfonyl compounds have been previously disclosed for uses unrelated to the present invention. For example, Pawloski et al., U.S. Pat. No. 5,480,568 disclose aryl triflouromethyl sulfonyl compounds for use as high temperature lubricants for magnetic recording media. Haug et al., U.S. Pat. No. 5,117,038 disclose triflouromethyl phenoxyphenylpropionic acid derivatives as herbicides. Others, namely Haga et al., U.S. Pat. No. 4,985,449 disclose trifluoromethyl sulfonyl phenoxy compounds for use as pesticides. Markley et al., U.S. Pat. No. 4,349,568, disclose triflouromethyl sulfonyl diphenyl ethers for use as antiviral agents. Reisdorff et al., U.S. Pat. No. 3,966,725, disclose triflouromethyl sulfonyl 1,3,5-triazine derivatives as coccidiostats. Others disclose aryl triflouromethyl sulfonyl compounds with a single nitrogen atom as a linker between the aromatic rings as herbicides. Examples of such compounds include Serban et al., EP 13144; Hartmann et al., U.S. Pat. No. 4,459,304 (insecticides, bactericides and fungicides). Still others have disclosed compounds with a single sulfur atom linker between the aromatic rings as synthetic intermediates to prepare trifluoromethyl sulfonyl substituted piperazinyl-benzothiazepines for use as sedatives, tranquilizers, antidepressants, and antiemetics (Schmutz et al., GB 1411587). Young et al., EP 233763, disclose sulfur linked quinolinyl trifluoromethyl sulfonyl compounds for use as a leukotriene antagonists.
Also, trifluoromethyl sulfonamido compounds have been previously disclosed for uses unrelated to the present invention. Hall et al., U.S. Pat. No. 5,405,871, disclose aryl trifluoromethyl sulfonamido hydrazones for use as pesticides. Takano et al., U.S. Pat. No. 4,954,518, disclose oxygen linked trifluoromethyl sulfonamido compounds for use as anti-inflammatory agents. Similarly, Adams et al., U.S. Pat. No. 5,545,669, disclose single oxygen linked trifluoromethyl sulfonamido compounds for use as phospholipase A2 inhibitors. Landes et al., WO97/10714, disclose sulfone linked aryl trifluoromethyl sulfonamido compounds for use as herbicides. Blaschke et al., WO97/03953, disclose sulfur linked aryl trifluoromethyl sulfonamido compounds for use as cyclo-oxygenase II inhibitors. Matsuo et al., U.S. Pat. No. 5,034,417, disclose alkanesulfonanilides as anti-inflammatory and analgesic agents.
In addition, methylene linked aryl trifluoromethyl sulfonyl compounds have been previously disclosed for uses unrelated to the present invention. Specifically, Fukada et al., WO 97/11050 and Toriyabe et al., 5,728,699, disclose methylene linked trifluoromethyl sulfonyl benzophenone and hydrazone as pesticides.
Although a great deal of information has been described about signal transduction and protein target associated therewith, there remains a need for drugs that effectively interact with these treat disease. Such drugs may be discovered from compounds published in the literature or novel compounds yet to be synthesized.
One aspect of this invention relates to, inter alia, novel trifluoromethyl sulfonyl and trifluoromethyl sulfonamido compounds and the physiologically acceptable salts and the prodrugs thereof and the use of these compounds to modulate the activity of enzymes associated with cellular signal transduction, and in particular, kinases and phosphatases, and in more particular, protein tyrosine phosphatases. Further, the invention encompasses that use of these compounds in the prevention and treatment of certain disorders including, but not limited to, disorders associated with phosphate binding proteins, including abnormal protein tyrosine enzyme related cellular signal transduction, such as cancer, diabetes, immuno-modulation, neurologic degenerative diseases, osteoporosis and infectious diseases.
Thus, the invention encompasses trifluoromethyl sulfonyl and trifluoromethyl sulfonamido compounds which are useful for the prevention or treatment of neoplastic diseases, diabetes (type I and II), and autoimmune diseases. The compounds of the invention are membrane permeable, easily synthesized using standard materials and potent and selective for inhibiting certain phosphate binding proteins, including phosphatases (e.g. PTP SHP2, 1B, Epsilon, MEG2, Zeta, Sigma, PEST, Alpha, Beta, Mu, DEP1 vide supra). This invention includes salts and prodrugs and other equivalents thereof, pharmaceutical compositions containing these and methods of their use.
In one embodiment, the invention is directed to compounds having the formula: 
or a pharmaceutically acceptable salt or solvate thereof, wherein:
Q is CF3SO2, CF3SO2NR3, CF3SO2R4 or CF3SO2N(R3)R4, wherein R3 is H, alkoxy, acyl or C1-C3 alkyl, each of which may be substituted or unsubstituted, and R4 is methylene which may be substituted or unsubstituted;
each R1 is independently C1-C3 alkyl, C1-C3 haloalkyl (for example, but not limited to, CF3, CC13), CN, (Cxe2x95x90O)OR, (Cxe2x95x90O)R5, H, halo, O(Cxe2x95x90O)R, OR, OH, NHR, NH(Cxe2x95x90O)OR, NH(Cxe2x95x90O)R5, NO2, NHSO2R5, SO2R5, R4SO2CF3 or tetrazole, wherein R5 is CF3, C1-C3 alkyl, NHR and wherein R is H, C1-C3 alkyl, aryl or heteroaryl, which may be substituted or unsubstituted;
each R2 is independently C1-C3 alkyl, C1-C3 haloalkyl (for example, but not limited to, CF3, CC13), CN, (Cxe2x95x90O)OR, (Cxe2x95x90O)R5, H, halo, O(Cxe2x95x90O)R, OR, OH, NHR, NH(Cxe2x95x90O)OR, NH(Cxe2x95x90O)R5, NO2, NHSO2R5, SO2R5. tetrazole, or X1-R6-X2 wherein X1 may be present or absent and if present is O, N, (Cxe2x95x90O), (Cxe2x95x90O)NH, NH(Cxe2x95x90O), SO2NH, NHSO2; R6 is C1-3 alkylene which may be substituted or unsubstituted; X2 is CF3, (Cxe2x95x90O)OR, (Cxe2x95x90O)R5, H, NH(Cxe2x95x90O)R5, NH(Cxe2x95x90O)OR, NHSO2R5, NRR3, O(Cxe2x95x90O)R, OR, SO2R5, tetrazole;
each n is independently from 0 to 3;
Ring B is an aryl, carbocyclic, heteroaryl, heterocyclic or phenyl ring which may be substituted or unsubstituted;
A1 is a linkage in which the shortest path is 2-8 atoms in length wherein the atoms in the linkage are carbon which may be substituted or unsubstituted or the carbon replaced with a single nitrogen or oxygen, or combination of nitrogen, oxygen and sulfur provided no two heteroatoms are adjacently linked in a linear linkage; the linkage may be or may contain an aryl, carbocyclic, heteroaryl, heterocyclic or a phenyl ring, which may be directly in the linkage or appended to the linkage; the linkage may be acylalkyl, alkenylene, alkoxy, alkoxyalkyl, alkoxyamino (xe2x80x94Oxe2x80x94Rxe2x80x94Nxe2x80x94), alkoxyarylalkoxy (xe2x80x94Oxe2x80x94Rxe2x80x94Arxe2x80x94Rxe2x80x94Oxe2x80x94, R is C1), alkoxyarylalkyl (xe2x80x94Oxe2x80x94Rxe2x80x94Arxe2x80x94Rxe2x80x94, R is C1-2), alkoxyarylamino (xe2x80x94Oxe2x80x94Rxe2x80x94Arxe2x80x94Nxe2x80x94, R is C1-2), alkoxyaryloxyalkyl (xe2x80x94Oxe2x80x94Rxe2x80x94Arxe2x80x94Oxe2x80x94Rxe2x80x94, R is C1), alkylamino, alkylaminoalkyl, alkylaminoarylaminoalkyl (xe2x80x94Rxe2x80x94Nxe2x80x94Arxe2x80x94Nxe2x80x94Rxe2x80x94, R is C1), alkylaryl, alkylarylalkyl, alkylarylamino (xe2x80x94Rxe2x80x94Arxe2x80x94Nxe2x80x94, R is C1-3), alkylaryloxy (xe2x80x94Rxe2x80x94Arxe2x80x94Oxe2x80x94, R is C1-3), alkylene, alkylenediamine, alkylenedioxy, alkyloxy (xe2x80x94Rxe2x80x94Oxe2x80x94), alkyloxyaryl, alkyloxyarylalkyloxy (xe2x80x94Rxe2x80x94Oxe2x80x94Arxe2x80x94Rxe2x80x94Oxe2x80x94, R is C1), alkyloxyaryloxyalkyl (xe2x80x94Rxe2x80x94Oxe2x80x94Arxe2x80x94Oxe2x80x94Rxe2x80x94, R is C1), C1-C6 alkylsulfonylamino, alkylthio, alkylthioalkyl, alkynylene, C1-C6 N-sulfonamido (xe2x80x94Nxe2x80x94SO2xe2x80x94Rxe2x80x94, R is C1-6), C3-C7 N-amido (xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94Rxe2x80x94, R is C2-6), aminoalkyl (xe2x80x94Nxe2x80x94Rxe2x80x94), aminoalkylamino, aminoalkylarylalkyl (xe2x80x94Nxe2x80x94Rxe2x80x94Arxe2x80x94Rxe2x80x94, R is C1-2), aminoalkylarylalkylamino (xe2x80x94Nxe2x80x94Rxe2x80x94Arxe2x80x94Rxe2x80x94Nxe2x80x94, R is C1), aminoalkylaryloxy (xe2x80x94Nxe2x80x94Rxe2x80x94Arxe2x80x94Oxe2x80x94, R is C1-2), aminoalkyloxy (xe2x80x94Nxe2x80x94Rxe2x80x94Oxe2x80x94), aminoaryl (xe2x80x94Nxe2x80x94Arxe2x80x94), aminoarylalkyl (xe2x80x94Nxe2x80x94Arxe2x80x94Rxe2x80x94, R is C1-3), aminoarylcarbonyl (xe2x80x94Nxe2x80x94Arxe2x80x94(Cxe2x95x90O)xe2x80x94), aminoaryloxy (xe2x80x94Nxe2x80x94Arxe2x80x94Oxe2x80x94), aminoaryloxyalkyl (xe2x80x94Nxe2x80x94Arxe2x80x94Oxe2x80x94Rxe2x80x94, R is C1-2), aminoarylsulfonyl (xe2x80x94Nxe2x80x94Arxe2x80x94SO2-), aryl, arylamino, ortho or para aryldioxy (xe2x80x94Oxe2x80x94Arxe2x80x94Oxe2x80x94), substituted meta-aryldioxy, aryldiamine (xe2x80x94Nxe2x80x94Arxe2x80x94Nxe2x80x94), aryloxy, aryloxyalkyl (xe2x80x94Oxe2x80x94Arxe2x80x94Rxe2x80x94, R is C1-3), aryloxyamino (xe2x80x94Oxe2x80x94Arxe2x80x94Nxe2x80x94), aryloxyaminoalkyl (xe2x80x94Oxe2x80x94Arxe2x80x94Nxe2x80x94Rxe2x80x94, R is C1-2), aryloxycarbonyl (xe2x80x94Oxe2x80x94Arxe2x80x94(Cxe2x95x90O)xe2x80x94), aryloxysulfonyl (xe2x80x94Oxe2x80x94Arxe2x80x94SO2-), benzimidazole, benzo[b]furan, benzo[b]thiophene, C3-C7 C-amido (xe2x80x94(Cxe2x95x90O)xe2x80x94Nxe2x80x94Rxe2x80x94, R is C2-7), carbonylarylamino (xe2x80x94(Cxe2x95x90O)xe2x80x94Arxe2x80x94Nxe2x80x94), carbonylarylcarbonyl (xe2x80x94(Cxe2x95x90O)xe2x80x94Arxe2x80x94(Cxe2x95x90O)xe2x80x94), carbonylaryloxy (xe2x80x94(Cxe2x95x90O)xe2x80x94Arxe2x80x94Oxe2x80x94), chromene, cycloalkylene, disulfidc, furan, haloalkyl, imidazole, imidazolidine, imidazoline, indole, isothiazole, isoxazole, morpholine, oxadiazole, oxazole, oxirane, parathiazine, phenothiazine, piperazine, piperidine, purine, pyran, pyrazine, pyrazole, pyrazolidine, pyrimidine, pyridine, pyrrole, pyrrolidine, quinoline, C2-C6 S-sulfonamido (xe2x80x94SO2-Nxe2x80x94R, R is C2-6), sulfonylalkyl, sulfonylarylamino (xe2x80x94SO2-Arxe2x80x94Nxe2x80x94), sulfonylaryloxy (xe2x80x94SO2-Arxe2x80x94Oxe2x80x94), sulfonylarylsulfonyl (xe2x80x94SO2-Arxe2x80x94SO2-), thiadiazole, thiazole, thiophene, triazine, triazole, unsubstituted azeridine, C3-C6 ureido (xe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x94Nxe2x80x94Rxe2x80x94, R is C2-5), which may be substituted or unsubstituted;
A2 is a linkage in which the shortest path is 0-6 atoms in length wherein the atoms in the linkage are carbon which may be substituted or unsubstituted or the carbon replaced with a single nitrogen, oxygen or sulfur, or combination of nitrogen, oxygen and sulfur; the linkage may be or may contain an aryl, carbocyclic, heteroaryl, heterocyclic or a phenyl ring, which may be directly in the linkage or appended to the linkage; the linkage may be single atom C, O, S or N which may be substituted or unsubstituted; the linkage may be acylalkyl, alkenylene, alkoxy, alkoxyalkyl, alkoxyamino, alkoxyarylalkoxy, alkoxyarylalkyl, alkoxyarylamino, alkoxyaryloxyalkyl, alkylamino, alkylaminoalkyl, alkylaminoarylaminoalkyl, alkylaryl, alkylarylalkyl, alkylarylamino, alkylaryloxy, alkylene, alkylenediamine, alkylenedioxy, alkyloxy, alkyloxyaryl, alkyloxyarylalkyloxy, alkyloxyaryloxyalkyl, alkylsulfonylamino, alkylthio, alkylthioalkyl, alkynylene, N-sulfonamido, N-amido, aminoalkyl, aminoalkylamino, aminoalkylarylalkyl, aminoalkylarylalkylamino, aminoalkylaryloxy, aminoalkyloxy, aminoaryl, aminoarylalkyl, aminoarylcarbonyl, aminoaryloxy, aminoaryloxyalkyl, aminoarylsulfonyl, aryl, arylamino, ortho or para aryldioxy, substituted meta-aryldioxy, aryldiamine, aryloxy, aryloxyalkyl, aryloxyamino, aryloxyaminoalkyl, aryloxycarbonyl, aryloxysulfonyl, benzimidazole, benzo[b]furan, benzo[b]thiophene, C-amido, carbonylarylamino, carbonylarylcarbonyl, carbonylaryloxy, chromene, cycloalkylene, furan, haloalkyl, imidazole, imidazolidine, imidazoline, indole, isothiazole, isoxazole, morpholine, oxadiazole, oxazole, oxirane, parathiazine, phenothiazine, piperazine, piperidine, purine, pyran, pyrazine, pyrazole, pyrazolidine, pyrimidine, pyridine, pyrrole, pyrrolidine, quinoline, sulfonamido, sulfonylalkyl, sulfonylarylamino, sulfonylaryloxy, sulfonylarylsulfonyl, thiadiazole, thiazole, thiophene, triazine, triazole, unsubstituted azeridine, ureido, which may be substituted or unsubstituted.
In another embodiment, the invention is directed to compounds having the formula (I), (II) above or a pharmaceutically acceptable salt or solvate thereof, wherein:
Q is CF3SO2;
each R1 is independently CF3, (Cxe2x95x90O)OR, (Cxe2x95x90O)R5, H, halo, NHR, NH(Cxe2x95x90O)OR, NH(Cxe2x95x90O)R5, NHSO2R5, NO2, O(Cxe2x95x90O)R, OH, OR, SO2R5 or tetrazole;
each R2 is independently (Cxe2x95x90O)OR, (Cxe2x95x90O)R5, NH(Cxe2x95x90O)OR, NH(Cxe2x95x90O)R5, NHR, NHSO2R5, NO2, xe2x80x94R6xe2x80x94(Cxe2x95x90O)OR, xe2x80x94R6-NRR3, xe2x80x94R6-tetrazole, or tetrazole;
each n is independently from 0 to 2;
Ring B is phenyl or heteroaryl which may be substituted or unsubstituted; and
linkage A1 is C2-C4 alkoxy, C2-C4 alkoxyalkyl, C2-C4 alkylenedioxy, C2-C4 alkylaminoalkyl, C2-C4 alkylenediamine, C3-C4C-amido, C3-C4 N-amido, C3-C4 ureido, C1-C3 N-sulfonamido, C2-C3 S-sulfonamido, aryldioxy, aryldiamine, aryl, alkylarylalkyl, imidazole, oxazole, oxadiazole, pyrazole, pyrazolidine, pyrrole or triazole.
In another embodiment, the invention is directed to compounds having the formula (I), (II) above or a pharmaceutically acceptable salt or solvate thereof, wherein:
Q is CF3SO2NH;
each R1 is independently CF3, (Cxe2x95x90O)OR, (Cxe2x95x90O)R5, H, halo, NHR, NH(Cxe2x95x90O)OR, NH(Cxe2x95x90O)R5, NHSO2R5, NO2, O(Cxe2x95x90O)R, OH, OR, SO2R5 or tetrazole;
each R2 is independently (Cxe2x95x90O)OR, (Cxe2x95x90O)R5, NH(Cxe2x95x90O)OR, NH(Cxe2x95x90O)R5, NHR, NHSO2R5, NO2, SO2R5, xe2x80x94R6xe2x80x94(Cxe2x95x90O)OR, xe2x80x94R6xe2x80x94NRR3, xe2x80x94R6-tetrazole, or tetrazole;
each n is independently from 0 to 2;
Ring B is phenyl or heteroaryl which may be substituted or unsubstituted; and
linkage A1 is C2-C4 alkoxy, C2-C4 alkoxyalkyl, C2-C4 alkylenedioxy, C2-C4 alkylaminoalkyl, C2-C4 alkylenediamine, C3-C4C-amido, C3-C4 N-amido, C3-C4 ureido, C1-C3 N-sulfonamido, C2-C3 S-sulfonamido, aryldioxy, aryldiamine, aryl, alkylarylalkyl, imidazole, oxazole, oxadiazole, pyrazole, pyrazolidine, pyrrole or triazole.
In another embodiment, the invention is directed to compounds having the formula: 
or a pharmaceutically acceptable salt or solvate thereof, wherein: Q is CF3SO2 or
CF3SO2NH; R1 is H or NO2; R2 is (Cxe2x95x90O)OR, NHSO2R5 or SO2R5; and the linkage A1 is C2-C4 alkoxyalkyl, aryldioxy, aryl, alkylarylalkyl or oxadiazole.
In another embodiment, the A1 linker in the compound having formula I or IV above the linker has the structure: 
where R is any substituent other than hydrogen.
The invention also includes pharmaceutical compositions comprising a compound of formula (I), (II) or (II). Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
Based in part upon an investigation of the activity of the above compounds in both biochemical and cellular assays, we have discovered that compounds having a trifluoromethylsulfonyl moiety and its derivative trifluoromethylsulfonamido have a broad spectrum of activity. Presently, without being limited by any specific mechanism of action, such compounds mimic the effects of the phosphate group for a wide variety of phospho-derivatives including proteins such as phosphatases and kinases, e.g., phosphotyrosine, thus providing inhibition of a variety of important therapeutic targets. The compounds of the invention are stable to phosphatase, capable of crossing cell membranes and readily prepared in high purity. Thus, these compounds are uniquely suitable for use as medicaments.
The compounds and pharmaceutical compositions of the invention can be used for treating, alleviating or preventing diseases, including but not limited to, diabetes mellitus; immune disorders in which cytokine signal transduction is deficient specifically anemia and immunodeficiency; rheumatoid arthritis; neurodegenerative diseases; cancer, particularly solid tumors, such as glioma, melanoma, Kaposi""s sarcoma, hemangioma and ovarian, breast, lung, pancreatic, liver, prostate, colon and epidermoid cancer, in which the malignant cells proliferate and/or metastasize as a result of uncontrolled signal transduction mediated by growth factors; infectious diseases associated with PTPases; or osteoporosis.
In addition, this invention provides a method for inhibiting, regulating or modulating the activity of a phosphate binding protein in a cell which comprises administering to the cell an effective amount of a compound with a molecular weight less than 2000 daltons, or a pharmaceutically acceptable salt or solvate thereof. The compound contains at least one functional group selected from the group consisting of C(R11)FaSObZxe2x80x94 and R12SObC(R11)Fmxe2x80x94; wherein a is 1, 2 or 3 and b is 1 or 2 and m is 1 or 2; Z is C or N; wherein R11 may be present or absent and if present is independently H, halo, C1-C4 alkyl, C2-C4 alkenyl or C1-C4 haloalkyl, which may be substituted or unsubstituted; wherein R12 is C1-C3 haloalkyl, C1-C3 alkyl which may be substituted or unsubstituted, or N which may be substituted or unsubstituted.
In this embodiment, the compound regulates, inhibits or modulates the activity of the phosphate binding protein.
In one embodiment of the above method the compound has the formula: C(R11)FaSObZR13 or R12SObC (R11)FmR3 ZR13 or R13 may be an amide, an amine, an ester, an ether, a monocyclic heterocycle, a polycyclic heterocycle, an acyclic hydrocarbon, a monocyclic aliphatic hydrocarbon, a polycyclic aliphatic hydrocarbon, a monocyclic aromatic hydrocarbon, a polycyclic aromatic hydrocarbon, a macrocycle, a nucleoside, a nucleotide, an oligoamide, an oligoamine, an oligoester, an oligoether, an oligonucleotide, an oligosaccharide, an oligourea, an oligourethane, a peptide, a peptide oligomer, a saccharide, a steroid, a urea, a urethane, which may be substituted or unsubstituted.
In a preferred embodiment, the compound contains the formula CF3SO2xe2x80x94, CF3SO2Nxe2x80x94, CF3SO2Cxe2x80x94, CF3SO2COxe2x80x94, CF3SO2CNxe2x80x94, CF3CF2SO2xe2x80x94 or CHF2SO2xe2x80x94.
In another preferred embodiment, ZR13 or R13 is a monocyclic heterocycle, a polycyclic heterocycle, a monocyclic aromatic hydrocarbon, a polycyclic aromatic hydrocarbon which may be substituted or unsubstituted. Alternatively, Z is methylene which may be substituted or unsubstituted. The molecular weight of the compound maybe less than 1000 daltons, preferably less than 650 daltons.
In the method above, the phosphate binding protein may be a phosphohistidine, phosphoserine, phosphothreonine or phosphotyrosine binding protein. It may also be an enzyme. The enzyme may be a metalloproteinase or an enzyme that forms a covalent phosphocysteine intermediate. The enzyme may be a phosphatase or a kinase such as a histidine kinase, a serine kinase, a threonine kinase or a tyrosine kinase. It may also be associated with protein tyrosine phosphatase signal transduction.
In one embodiment of the method, the phosphate binding protein is a dual-specificity phosphatase, histidine/lysine phosphatase, low-molecular weight phosphatase, a phosphotyrosine binding (PTB) domain, a pleckstrin homology domain, a Ser/Thr phosphatase, a Src homology 2 (SH2) domain, a protein tyrosine phosphatase, or a tyrosine-specific phosphatase. The phosphatase may be Alpha phosphatase, Beta phosphatase, cdc25 phosphatase, cdi phosphatase, CD45 phosphatase, DEPI phosphatase, Epsilon phosphatase, LAR phosphatase, MAP kinase phosphatase, MEG2 phosphatase, Mu phosphatase, 1B phosphatase, PEST phosphatase, PP2xcex2(calcineurin) phosphatase, SHPI phosphatase, SHP2 phosphatase, Sigma phosphatase, T-cell phosphatase, VH1-like phosphatase, VHR phosphatase, Yersinia phosphatase, or Zeta phosphatase.
Preferably, the activity of the phosphate binding protein is determined by an in vitro assay. In addition, preferably the cell is a mammalian cell, more preferably a human cell.